Alpha-glucoside formation of xenobiotics by rat liver alpha-glucosidases

Abstract

We investigated enzymes participating in alpha-glucoside formation, a novel metabolic pathway of xenobiotics in a metabolic study of indeloxazine hydrochloride in rats. When rat tissue homogenates and the indeloxazine metabolite trans-4-(2-morpholinylmethoxy)-1,2-indandiol (M-2) were incubated, M-2-alpha-glucoside formation was observed in liver. This reaction was almost completely inhibited by the alpha-glucosidase inhibitor acarbose. The liver homogenate was then separated into subcellular fractions and an acid alpha-glucosidase in lysosomes and two neutral alpha-glucosidases in microsomes and cytosol were partially purified. The chromatographic behavior and optimum pH of the glucosyltransferase activity of each of the enzyme preparations were almost identical with those of alpha-glucosidase (hydrolase) activity of the same specimen, suggesting the former activity to be also due to alpha-glucosidase. Agreeing with their hydrolytic substrate specificities, the acid enzyme transferred glucose to M-2 from a series of glucose derivatives, ranging from low molecular maltosaccharides to high molecular glycogen, whereas the neutral enzymes took only low molecular maltosaccharides as glucosyl donors. These results led to the conclusion that the formation of alpha-glucoside conjugates is catalyzed by more than one alpha-glucosidase in the liver and uses maltosaccharides or glycogen as glucosyl donors. Several other diol structure-bearing compounds were found in vitro to give rise to alpha-glucoside conjugates, and the mechanism of alpha-glucoside formation is discussed.